The SardiNIA study population cohort comprises over 7,000 subjects, starting at ages from 14-102, from a cluster of four towns in Sardinia. The study has been measuring >300 quantitative traits (endophenotypes or quantitative risk-related genetic or environmental factors) that can be scored on a continuous scale, and is designed as a longitudinal studies, with 4 visits over the first 13 years of its tenure. Traits of special interest include a range of cardiovascular risk factors, anthropometric measurements, blood test values, and facets of personality. Fourth visits are now in progress for the study cohort to permit the assessment of longitudinal trends and outcomes, as well as the assessment of additional phenotypes related to bone density and frailty as a function of age. For example, 24 hour blood pressure measurements and ECHOcardiography are extending the analysis of cardiovascular traits; and the cohort is being specifically extended to over 250 individuals over 92 years of age to analyze effects of extreme age. With this cohort, a variety of epidemiological and genetic factors have been identified. In the last year, epidemiological studies have been done of personality traits associated with white coat or masked hypertension, with circadian blood pressure patterns, or with uric acid levels; of the prevalence of chronic kidney disease and unknown thyroid disorders; and of arterial stiffness and influences of the metabolic syndrome. As for genetic studies, full-genome scans with batteries of single-nucleotide markers were conducted, and were supplemented in the last year with full genome DNA sequencing and genotyping with specialized chips (metabochip, immunochip, and exome chip, and a chip designed to give equal coverage across the entire genome). These have provided a catalogue of over 17,000,000 variants, including a range of relatively rare variants, which are being tested for association with traits and diseases in Genome-wide association scans (GWAS). In addition, 3,500 individuals have provided lymphocyte samples for analysis (see below). In studies thus far, GWAS have pointed to genes/variants that determine a significant portion of the genetic contribution to variance for each trait and disease studied. In conjunction with consortium efforts on other population cohorts, including the Baltimore Longitudinal Study of Aging and the InCHIANTI study supported by the NIA, an increasing number of publications have resulted that identify genes associated with obesity, cardiovascular traits, and levels of lipids and blood components. In particular, genes associated with HbF levels as a modulator of thalassemia/sickle cell disease severity have been identified, as well as findings of genetic factors determining loci for blood pressure, many affecting adiposity; and personality facets affecting under- and over-weight. In the past year, some GWAS consortium studies have advanced technical approaches, including the usefulness of averaging of quantitative blood pressure traits; quality control; integrative annotation of variants; and mining the human phenome using allelic scores. As for GWAS of genetic factors involved in traits and diseases, Consortium efforts in the last year have discovered variants associated with the QT interval; thyroid peroxidase antibodies and clinical thyroid disease; fibrinogen levels; and BMI in adolescents and young adults. Supporting the range and depth of results are 3 of the most recent publications: in one, human demographic history was reconstructed from DNA sequences of 1,204 Y chromosomes in the cohort; a second inferred DNA variants that control up to 80% of the variability of at least one of 95 separated immune cell types; and a third identified a genetic locus that is associated with part of hereditary capacity for educational attainment. In detail, in a new initiative in the past two years, separation of 95 types of immune system cells was done for 3,400 individuals by flow-sorting to determine levels of general leukocyte sub-populations (B and T, natural killer, monocytes, etc.) and subclasses of T-regulatory cells, dendritic cells, and T cell maturation stages; the variation of levels of many cell types especially Tregs is up to 87% genetically determined; and GWAS analysis on 1,200 individuals with the 12,500,000 SNP set then revealed 23 with a large effect on at least one cell type. For example, the R262W SH2B3 variant, already associated with several autoimmune diseases and negative regulation of hematopoiesis, was shown to particularly affect the numbers of CD4+ T cells, likely resulting in a loss of function. This year GWAS power was greatly augmented by sequencing the genomes of the cohort, recovering rare and Sardninai specific variants that increased the numbers of variants from 2.5 million to over 17.5 million. In 3 publications; this has resulted in The development of genome-wide sequencing technology now enables SardiNIA researchers to analyze over 17 million gene variants to determine whether they are associated with disease risk and other traits. Findings from this complete-variant analysis are reported in the Nature Genetics papers: Height -- Two new gene variants were found to have a significant effect on stature in Sardinians. Together, they appear to reduce height by 6 centimeters. Researchers found additional height-decreasing gene variants consistently across the Sardinian population that reflect an observed island effect in which large, island-dwelling mammals decrease in size over time. Lipids and Inflammation -- Researchers identified 14 novel genetic variants associated with serum lipid levels, as well as 19 associated with inflammatory markers in the blood. Both lipid levels and inflammatory markers influence risk of heart disease. Hemoglobin -- For the first time, researchers concurrently analyzed gene regulation of A1, A2 and fetal hemoglobin levels, to see if there was any coordination in their regulation. Twenty-three associations were seen at 10 loci, including five new gene candidates. Half the variants showed associations with more than one type of hemoglobin. Hemoglobin deficiency can cause life-threatening diseases like beta-thalassemia and sickle cell anemia. In a complementary approach, cohorts of Sardinian patients and controls were assembled and genotyped for GWAS for each of several diseases, Type 1 diabetes, multiple sclerosis (MS), and breast cancer. GWAS with approximately 6.6 million SNPs in over 3,000 patients and 3,500 controls identified CBLB as associated with MS. CBLB involvement in MS was technically easier to find in Sardinia, but has now been widely replicated in other patient cohorts. Our analyses extend associations of variants with a disease to specify the cell types in which the alleles have their effects. This provides a further step in supplying markers and potential molecular and cellular targets for possible eventual intervention.